This application is a 371 application of PCT/JP 99/06655 filed Nov. 29, 1999.
1. Technical Field
The present invention relates to a process for producing a quinolinecarbaldehyde. More particularly, it relates to a process for easily and efficiently producing 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde which is useful as an intermediate for the synthesis of a HMG-CoA reductase inhibitor as a cholesterol-lowering drug.
2. Background Art
2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde is an intermediate useful as an intermediate for the synthesis of a HMG-CoA reductase inhibitor. Heretofore, as a method of oxidizing 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline to 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, an oxidation method employing chromic acid or a method of employing a dimethyl sulfoxide-dehydration agent (such as a Swern oxidation method), or a method of employing a nitroxyl radical-hypochlorite represented by TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radicals), has been used.
However, the above methods have a problem of waste liquid treatment due to formation of environmentally hazardous chromium ions or a problem of e.g. formation of badly smelling dimethyl sulfide, and in the case of nitroxyl radicals, the reagent is expensive and has a difficulty also in the chemical stability, and such can not be regarded as an industrially advantageous reaction.
Accordingly, the object of the present invention is to provide a process for simply and industrially advantageously producing 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde by oxidizing 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline.
The present inventors have studied various oxidation methods to solve such problems, and as a result, have found a production process which is free from the above-mentioned problem of waste liquid treatment or bad odor and which provides a good yield and is industrially advantageous, and they have arrived at the present invention.
Namely, the present invention provides a process for producing 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde of the formula (III): 
characterized by oxidizing 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline of the formula 
with a salt of a hypohalogenous acid in the presence of a quaternary ammonium salt of the formula (II): 
wherein each of R1, R2, R3 and R4 which are the same or different from one another, is a C1-16 alkyl group or a benzyl group (the benzyl group may be substituted by a C1-4 alkyl group, a C1-4 alkoxy group or a halogen atom), and Xxe2x88x92 is a halogen ion, a sulfate ion or a methanesufonate ion.
According to the present invention, 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde which is a useful intermediate for the synthesis of a HMG-CoA reductase inhibitor, can be produced in good yield and industrially advantageously.
Now, the present invention will be described in further detail.
Firstly, the terms for the respective substituents of R1 R2, R3, R4 and Xxe2x88x92 will be explained.
In this specification, xe2x80x9cnxe2x80x9d means normal, xe2x80x9cixe2x80x9d iso, xe2x80x9csxe2x80x9d secondary, xe2x80x9ctxe2x80x9d tertiary, xe2x80x9ccxe2x80x9d cyclo, and xe2x80x9coxe2x80x9d ortho.
The C1-4 alkyl group includes linear, branched and cyclic alkyl groups and may, for example, be methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-methyl-c-propyl and 2-methyl-c-propyl, preferably methyl and ethyl.
The C1-16 alkyl group includes linear, branched and cyclic alkyl groups and may, for example, be methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2-ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl-n-propyl, 2-ethyl-2-methyl-n-propyl, c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4-dimethyl-c-butyl, 3,3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl-c-propyl, 2-i-propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c-propyl, 1-ethyl-2-methyl-c-propyl, 2-ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3-methyl-c-propyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl and n-hexadecyl.
The C1-4 alkoxy group includes linear, branched and cyclic alkoxy groups and may, for example, be methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, c-butoxy, 1-methyl-c-propoxy and 2-methyl-c-propoxy, preferably methoxy and ethoxy.
The halogen atom may, for example, be a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a chlorine atom and a bromine atom.
The halogen ion may, for example, be a fluorine ion, a chlorine ion, a bromine ion and an iodine ion, preferably a chlorine ion and a bromine ion.
The salt of a hypohalogenous acid may specifically be sodium hypochlorite, calcium hypochlorite, potassium hypochlorite and sodium hypobromite, preferably sodium hypochlorite, calcium hypochlorite and potassium hypochlorite.
Preferred R1, R2, R3 and R4 may be methyl, ethyl, n-propyl, i-propyl, n-butyl, n-octyl, n-dodecyl and benzyl.
Preferred Xxe2x88x92 may be a chlorine ion and a bromine ion.
The following process may be mentioned as a preferred process in the present invention.
(1) A process for producing 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde of the formula [III] characterized by oxidizing 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline of the formula [I] with sodium hypochlorite, calcium hypochlorite or potassium hypochlorite in the presence of a quaternary ammonium salt of the formula [II].
Now, a specific process for producing 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde will be explained.
The quaternary ammonium salt is added to a solution comprising 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline and a solvent for the reaction, followed by stirring, and the salt of a hypohalogenous acid is added thereto, followed by stirring, whereby the desired 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde can be produced.
The solvent for the reaction is not particularly limited so long as it does not affect the reaction. For example, nitrites such as acetonitrile, propionitrile and butylonitrile, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene and o-dichlorobenzene, aliphatic hydrocarbons such as n-hexane, cyclohexane, n-octane and n-decane, esters such as methyl acetate, ethyl acetate and propyl acetate, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether and dimethoxy ethane, an amide such as N,N-dimethylformamide, N,N-dimethylacetoamide and N-methyl pyrrolidone, ureas such as 1,3-dimethylimidazolidinone and tetramethyl urea, preferably esters such as methyl acetate, ethyl acetate and propyl acetate, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbons such as toluene and xylene, and ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, may, be mentioned.
Further, these solvents for the reaction may be used alone or in combination.
The amount of the solvent for the reaction to be used is within a range of from 1 to 200 times (w/w), preferably within a range of from 2 to 50 times (w/w), of the substrate (2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline).
The quaternary ammonium salts may not necessarily be used alone, and two or more of them may be used in combination. The amount of the quaternary ammonium salt is from 0.005 to 5 equivalents, preferably from 0.05 equivalent to 0.5 equivalent, based on the substrate.
The amount of the salt of a hypohalogenous acid is from 1.05 to 5 equivalents, preferably from 1.1 to 2 equivalents, based on the substrate.
The reaction temperature is within a range of from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from 10xc2x0 C. to 70xc2x0 C.
The reaction time varies depending upon the solvent to be used, the type and amount of the quaternary ammonium salt, the reaction temperature, etc. from the viewpoint of an industrial process, it is preferably within 8 hours.
After completion of the reaction, water is added, followed by extraction with a solvent for extraction, such as ethyl acetate, dichloromethane or toluene, drying and concentration under reduced pressure to obtain the desired 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde.
If necessary, recrystallization is carried out from a solvent for recrystallization, such as a methanol/water mixed solvent or a toluene/n-hexane mixed solvent, or crystals obtained by distilling off the solvent for extraction are washed with e.g. i-propyl ether or c-hexane, whereby 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde of high purity can be isolated.